Hemisphere lateralization of graph theoretical network in end-stage knee osteoarthritis patients.

Hemisphere functional lateralization is a prominent feature of the human brain. However, it is not known whether hemispheric lateralization features are altered in end-stage knee osteoarthritis (esKOA). In this study, we performed resting-state functional magnetic imaging on 46 esKOA patients and 31 healthy controls (HCs) and compared with the global and inter-hemisphere network to clarify the hemispheric functional network lateralization characteristics of patients. A correlation analysis was performed to explore the relationship between the inter-hemispheric network parameters and clinical features of patients. The node attributes were analyzed to explore the factors changing in the hemisphere network function lateralization in patients. We found that patients and HCs exhibited "small-world" brain network topology. Clustering coefficient increased in patients compared with that in HCs. The hemisphere difference in inter-hemispheric parameters including assortativity, global efficiency, local efficiency, clustering coefficients, small-worldness, and shortest path length. The pain course and intensity of esKOA were positively correlated with the right hemispheric lateralization in local efficiency, clustering coefficients, and the small-worldness, respectively. The significant alterations of several nodal properties were demonstrated within group in pain-cognition, pain-emotion, and pain regulation circuits. The abnormal lateralization inter-hemisphere network may be caused by the destruction of regional network properties.

Role and Therapeutic Potential for Targeting Fibroblast Growth Factor 10/FGFR1 in Relapsed Rheumatoid Arthritis.

OBJECTIVE: Fibroblast-like synoviocytes (FLSs) contribute to inflammation and joint damage in rheumatoid arthritis (RA). However, the regulatory mechanisms of FLSs in relapse and remission of RA remain unknown. Identifying FLS heterogeneity and their underlying pathogenic roles may lead to discovering novel disease-modifying antirheumatic drugs. METHODS: Combining single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, we sequenced six matched synovial tissue samples from three patients with relapse RA and three patients in remission. We analyzed the differences in the transcriptomes of the FLS subsets between the relapse and remitted phases. We validated several key signaling pathways using quantitative real-time PCR (qPCR) and multiplex immunohistochemistry (mIHC). We further targeted the critical signals in vitro and in vivo using the collagen-induced arthritis (CIA) model in rats. RESULTS: Lining and sublining FLS subsets were identified using scRNA-seq. Differential analyses indicated that the fibroblast growth factor (FGF) pathway was highly activated in the lining FLSs from patients with relapse RA for which mIHC confirmed the increased expression of FGF10. Although the type I interferon pathway was also activated in the lining FLSs, in vitro stimulation experiment suggested that it was independent of the FGF10 pathway. FGF10 knockdown by small interfering RNA in FLSs significantly reduced the expression of receptor activator of NF-κB ligand. Moreover, recombinant FGF10 protein enhanced bone erosion in the primary human-derived pannus cell culture, whereas the FGF receptor (FGFR) 1 inhibitor attenuated this process. Finally, administering an FGFR1 inhibitor displayed a therapeutic effect in a CIA rat model. CONCLUSION: The FGF pathway is a critical signaling pathway in relapse RA. Targeted tissue-specific inhibition of FGF10/FGFR1 may provide new opportunities to treat patients with relapse RA.

[Effect of 28-day administration of Psoraleae Fructus water extract on early liver injury in rats].

This study aims to investigate the hepatotoxicity of Psoraleae Fructus water extract and the underlying mechanism in rats. Forty-eight rats were randomly assigned into four groups: a blank group and low-(BZGL, 6.25 g·kg~(-1)), medium-(BGZM, 12.5 g·kg~(-1)), and high-dose(BGZH, 25 g·kg~(-1)) Psoraleae Fructus water extract groups. The rats were treated for 28 days, and toxicity and mortality were observed daily. After 28 days, the rats were sacrificed, and the body weight, liver index, and liver-to-brain ratio were calculated. The morphological changes in the liver tissue were observed, and the serum levels of related biochemical indicators were measured. The results showed that compared with the blank group, Psoraleae Fructus water extracts of different doses decreased the body weight, increased the liver index and liver-to-brain ratio, and caused liver hypertrophy and pathological changes. Pathological examination revealed that the rats in Psoraleae Fructus water extract groups had bile duct hyperplasia, inflammatory cell infiltration, and liver cell fibrosis. Compared with the blank group, BGZL elevated the levels of alanine transaminase(ALT), α-glutathione S-transferase(α-GST), and total bile acid(TBA)(P<0.05), and BGZM and BGZH elevated the levels of ALT, TBA, α-GST, γ-glutamyl transferase(γ-GT), purine nucleoside phosphorylase(PNP), ornithine carbamoyltransferase(OCT), and arginase(ArgI)(P<0.05). Compared with the blank group, Psoraleae Fructus water extracts of different doses down-regulated the mRNA and protein levels of bile salt export pump(BSEP) and farnesoid X receptor(FXR) and up-regulated the mRNA and protein levels of tumor necrosis factor-α(TNF-α), nuclear factor kappaB(NF-κB), and cholesterol 7 alpha-hydroxylase(CYP7A1)(P<0.05). The results suggested that Psoraleae Fructus water extract caused toxicity in rats, showing a dose-toxicity relationship. Psoraleae Fructus water extract may cause liver damage, which may be due to its effect on liver bile acid secretion and induction of inflammation.

The effect of JuanBiQiangGu granules in combination with methotrexate on joint inflammation in rheumatoid arthritis: a randomized controlled trial.

Background: Rheumatoid arthritis (RA) joint inflammation severely affects joint function and quality of life in patients and leads to joint deformities and limb disability. The non-steroidal anti-inflammatory drugs used in the treatment of RA do not fully control the progression of joint inflammation and bone destruction and have notable adverse reactions. Traditional Chinese medicine formula JuanBiQiangGu Granules (JBQG) are commonly used for the treatment of RA inflammation and delay of bone destruction, but has not been evaluated through high-quality clinical studies. There is a pressing need for well-designed, randomized, parallel, controlled clinical studies to evaluate the exact effect of JBQG on RA joint inflammation and improvement of patient quality of life. Methods: This is a randomized, parallel, controlled clinical study in which 144 patients with rheumatoid arthritis who met the inclusion criteria were randomly assigned to 2 groups in a 1:1 ratio. The JBQG group received methotrexate 7.5 mg qw and JBQG granules 8 mg tid, while the MTX group received methotrexate 7.5 mg qw. The endpoint was 12 weeks after treatment. Relevant indices at baseline, 4 weeks, 8 weeks, and 12 weeks after treatment were observed and recorded, and DAS28-ESR, HAQ-DI, and Sharp scores were recorded for each patient. Blood samples were collected to test for CRP, ESR, TNF-α, IL-1ß, IL-6, IL-17, and INF-γ, and adverse reactions and liver and kidney function (AST, ALT, Cr, BUN) were recorded for safety assessment. After 12 weeks of treatment, the effect of JBQG granules on disease activity, improvement in bone damage, and patient quality of life scores and safety in RA patients were evaluated. Results: A total of 144 subjects completed treatment (71 in the JBQG group and 73 in the MTX group) and were included in the analysis. At baseline, there were no significant differences between the groups in terms of the observed indicators (p > 0.05). After treatment, 76.06% of patients in the JBQG group had DAS28-ESR levels below or equal to Low, including 45.07% in Remission and 5.63% in High, compared to 53.1% in the MTX group below or equal to Low, 12.33% in Remission, and 17.81% in High. CRP was significantly reduced (8.54 ± 5.87 vs. 11.86 ± 7.92, p < 0.05, p = 0.005), ESR was significantly reduced (15.1 ± 6.11 vs. 21.96 ± 9.19, p < 0.0001), TNF-α was significantly reduced (1.44 ± 0.83 vs. 1.85 ± 1.07, p < 0.05, p = 0.011), IL-17 was significantly reduced (0.53 ± 0.33 vs. 0.71 ± 0.38, p < 0.05, p = 0.004), and INF-γ was significantly reduced (3.2 ± 1.51 vs. 3.89 ± 1.77, p < 0.05, p = 0.014). The median (IQR) OPG in the JBQG group was 2.54 (2.21-3.01), significantly higher than in the MTX group 2.06 (1.81-2.32), p < 0.0001), and the median (IQR) ß-CTX in the JBQG group was 0.4 (0.32-0.43), significantly lower than in the MTX group 0.55 (0.47-0.67), p < 0.0001). The median (IQR) VSA scores were 2 (1-3), a decrease from 3 (2-4) in the MTX group (p < 0.0001). The median (IQR) Sharp scores were 1 (1-2), a decrease from 2 (1-2) in the MTX group, but the difference was not statistically significant (p > 0.05, p = 0.28). The median (IQR) HAQ-DI scores were 11 (8-16), significantly lower than in the MTX group 26 (16-30) (p < 0.0001). The median (IQR) AST in the JBQG group was 16 (12-20), with a significant difference compared to the MTX group 19 (13-25) (p < 0.01, p = 0.004); the median (IQR) ALT in the JBQG group was 14 (10-18), with a significant difference compared to the MTX group 16 (11-22.5) (p < 0.05, p = 0.015). There were no statistically significant differences in Cr or BUN (p > 0.05). Conclusion: JuanBiQiangGu Granules can be used to treat patients with rheumatoid arthritis, alleviate joint inflammation, reduce the incidence of adverse reactions to methotrexate, and has good safety. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/index.html; identifier: ChiCTR2100046373.

Electroacupuncture alleviates pain after total knee arthroplasty through regulating neuroplasticity: A resting-state functional magnetic resonance imaging study.

INTRODUCTION: We aimed to evaluate the efficacy of electroacupuncture in relieving acute pain after total knee arthroplasty (TKA) and related mechanism. METHODS: In this randomized, single-blind, and sham-acupuncture controlled study. Forty patients with postoperative acute pain were recruited and randomly divided electroacupuncture group (n = 20) and sham-acupuncture group (n = 20) from November 2020 to October 2021. All patients received electroacupuncture or sham-acupuncture for 5 days after TKA. Their brain regions were scanned with resting-state functional magnetic resonance imaging before and after intervention. Pain was scaled. Another 40 matched healthy controls underwent scanning once. The amplitude of low-frequency fluctuation (ALFF) values was compared. Pearson's correlation analysis was utilized to explore the correlation of ALFF with clinical variables in patients after intervention. RESULTS: Compared with the HCs, patients with acute pain following TKA had significantly decreased ALFF value in right middle frontal gyrus, right supplementary motor area, bilateral precuneus, right calcarine fissure and surrounding cortex, and left triangular part of inferior frontal gyrus (false discovery rate corrected p < .05). Patients had higher ALFF value in bilateral precuneus, right cuneus, right angular gyrus, bilateral middle occipital gyrus, and left middle temporal gyrus after electroacupuncture (AlphaSim corrected p < .01). Correlation analysis revealed that the change (postoperative day 7 to postoperative day 3) of ALFF in bilateral precuneus were negatively correlated with the change of NRS scores (r = -0.706; p = .002; 95% CI = -0.890 to -0.323) in EA group. CONCLUSIONS: The functional activities of related brain regions decreased in patients with acute pain after TKA. The enhancement of the functional activity of precuneus may be the neurobiological mechanism of electroacupuncture in treating pain following TKA.

The Effectiveness of Tuina in Relieving Pain, Negative Emotions, and Disability in Knee Osteoarthritis: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the effectiveness of Tuina in relieving the pain, negative emotions, and disability of patients with knee osteoarthritis (KOA). DESIGN: Single-center, parallel, randomized controlled trial. SETTING: Shanghai Guanghua Integrated Chinese and Western Medicine Hospital, Shanghai, China. SUBJECTS: Adult patients with KOA who were able to speak Chinese and self-report symptoms were eligible. METHODS: A total of 104 patients were randomly allocated to receive the 6-week treatment of Tuina (Tuina group) or celecoxib (celecoxib group). Data on pain, negative emotions, and disability were collected at baseline, at week 2, 4, and 6, and follow-up (1 month after the last treatment). The primary outcomes were the pressure pain thresholds. The secondary outcomes were: (1) numerical rating scale at rest and with movement; (2) Hamilton Anxiety Scale; (3) Hamilton Depression Scale; (4) Western Ontario and McMaster Universities Osteoarthritis Index; and (5) clinical effective rate. The adverse events of the trial were evaluated. RESULTS: In total, 99 patients completed the follow-up. Generalized linear mixed models were constructed to analyse the between-group differences. Statistically significant differences were found in the interaction effects (P < .05). In evaluating the group effect, statistical differences were found at week 6 and follow-up (P < .05). Further, all variables showed a time effect (P < .05). A statistical difference in the clinical effective rate was found between the Tuina and celecoxib groups (P < .05). CONCLUSIONS: Tuina produced superior effects for pain, negative emotions, and disability over time, as compared to celecoxib in patients with KOA.

Cerebral mechanism of opposing needling for managing acute pain after unilateral total knee arthroplasty: study protocol for a randomized, sham-controlled clinical trial.

BACKGROUND: Opposing needling is a unique method used in acupuncture therapy to relieve pain, acting on the side contralateral to the pain. Although opposing needling has been used to treat pain in various diseases, it is not clear how opposing needling affects the activity of the central nervous system to relieve acute pain. We herein present the protocol for a randomized sham-controlled clinical trial aiming to explore the cerebral mechanism of opposing needling for managing acute pain after unilateral total knee arthroplasty (TKA). METHODS: This is a randomized sham-controlled single-blind clinical trial. Patients will be allocated randomly to two parallel groups (A: opposing electroacupuncture group; B: sham opposing electroacupuncture group). The Yinlingquan (SP9), Yanglingquan (GB34), Futu (ST32), and Zusanli (ST36) acupoints will be used as the opposing needling sites in both groups. In group A, the healthy lower limbs will receive electroacupuncture, while in group B, the healthy lower limbs will receive sham electroacupuncture. At 72 h after unilateral TKA, patients in both groups will begin treatment once per day for 3 days. Functional magnetic resonance imaging will be performed on all patients before the intervention, after unilateral TKA, and at the end of the intervention to detect changes in brain activity. Changes in pressure pain thresholds will be used as the main outcome for the improvement of knee joint pain. Secondary outcome indicators will include the visual analogue scale (including pain during rest and activity) and a 4-m walking test. Surface electromyography, additional analgesia use, the self-rating anxiety scale, and the self-rating depression scale will be used as additional outcome indices. DISCUSSION: The results will reveal the influence of opposing needling on cerebral activity in patients with acute pain after unilateral TKA and the possible relationship between cerebral activity changes and improvement of clinical variables, which may indicate the central mechanism of opposing needling in managing acute pain after unilateral TKA. TRIAL REGISTRATION: Study on the brain central mechanism of opposing needling analgesia after total kneearthroplasty based on multimodal MRI ChiCTR2100042429 . Registered on January 21, 2021.

Altered brain activity in end-stage knee osteoarthritis revealed by resting-state functional magnetic resonance imaging.

INTRODUCTION: Knee osteoarthritis (KOA) is characterized by a degenerative change of knee cartilage and secondary bone hyperplasia, resulting in pain, stiffness, and abnormal walking gait. Long-term chronic pain causes considerable cortical plasticity alternations in patients. However, the brain structural and functional alterations associated with the pathological changes in knee joints of end-stage KOA patients remain unclear. This study aimed to analyze the structural and functional connectivity alterations in end-stage KOA to comprehensively understand the main brain-associated mechanisms underlying its development and progression. METHODS: In this study, 37 patients with KOA and 37 demographically matched healthy controls (HCs) were enrolled. Alternations in gray matter (GM) volume in patients with KOA were determined using voxel-based morphometry. The region with the largest GM volume alteration was selected as the region of interest to calculate the voxel-wise resting-state functional connectivity (rs-FC) in the two groups. Pearson's correlation coefficient was used to analyze the correlation between clinical measures and GM volume alternations in patients with KOA. RESULTS: Compared with HCs, patients with KOAs exhibited significantly decreased GM volumes in the left middle temporal gyrus (left-MTG) and the left inferior temporal gyrus. Results of the voxel-wise rs-FC analysis revealed that compared with HCs, patients with KOA had decreased left-MTG rs-FC to the right dorsolateral superior frontal gyrus, left middle frontal gyrus, and left medial superior frontal gyrus. GM volume in the left-MTG was negatively correlated with the Western Ontario and McMaster Universities Arthritis Index in patients with KOA (r = -0.393, p = .016). CONCLUSION: Structural remodeling and functional connectivity alterations may be one of the central brain mechanisms associated with end-stage KOA.